Reproductive Factors and Serum Uric Acid Levels in Females from the General Population: The KORA F4 Study

Hyperuricemia is associated with an increased risk of metabolic and cardiovascular diseases. There are pronounced sex differences in the levels of uric acid. It is largely unknown whether or not reproductive parameters which induce hormonal changes are responsible for this. We examined if there are associations between reproductive parameters and uric acid levels in a female population-based sample. In this cross-sectional analysis, data of 1530 women aged 32 to 81 years participating in the KORA F4 study, conducted between 2006 and 2008 in Southern Germany were used. Reproductive parameters were obtained by standardized interviews. Uric acid levels were tested by the uricase method. The whole study sample and stratified in pre- and postmenopausal women was analyzed. Menopausal status and earlier age at menarche were associated with higher serum uric acid levels (age-adjusted: p-values 0.003, <0.001 respectively; after multivariable adjustment, including BMI: p-values 0.002, 0.036). A history of oral contraceptive use showed an association with uric acid levels only after multivariable adjustment (p-value 0.009). Hot flushes showed an association with uric acid levels only after age-adjustment (p-value 0.038), but lost significance after adding other confounders. Other reproductive factors, including parity, current or ever use of hormone replacement therapy, current use of oral contraceptives, hysterectomy, bilateral oophorectomy, or depressive mood related to menopausal transition were not associated with uric acid levels. Postmenopausal status, earlier age at menarche and a history of oral contraceptive use were independently associated with higher serum uric acid concentrations in women from the general population. Further studies, especially longitudinal population-based studies investigating the relationship of female reproductive parameters with uric acid levels are necessary to confirm our findings

Sexual violence and antiretroviral adherence among women of reproductive age in African population-based surveys: the moderating role of the perinatal phase

INTRODUCTION: Women face challenges in antiretroviral therapy (ART) adherence and achieving viral suppression despite progress in the expansion of HIV treatment. Evidence suggests that violence against women (VAW) is an important determinant of poor ART adherence in women living with HIV (WLH). In our study, we examine the association of sexual VAW and ART adherence among WLH and assess whether this association varies by whether women are pregnant/breastfeeding or not. METHODS: A pooled analysis was conducted among WLH from Population-Based HIV Impact Assessment cross-sectional surveys (2015-2018) from nine sub-Saharan African countries. Logistic regression was used to examine the association between lifetime sexual violence and suboptimal ART adherence (≥1 missed day in the past 30 days) among reproductive age WLH on ART, and to assess whether there was any evidence for interaction by pregnancy/breastfeeding status, after adjusting for key confounders. RESULTS: A total of 5038 WLH on ART were included. Among all included women, the prevalence of sexual violence was 15.2% (95% confidence interval [CI]: 13.3%-17.1%) and the prevalence of suboptimal ART adherence was 19.8% (95% CI: 18.1%-21.5%). Among only pregnant and breastfeeding women, the prevalence of sexual violence was 13.1% (95% CI: 9.5%-16.8%) and the prevalence of suboptimal ART adherence was 20.1% (95% CI: 15.7%-24.5%). Among all included women, there was evidence for an association between sexual violence and suboptimal ART adherence (adjusted odds ratio [aOR]: 1.69, 95% CI: 1.25-2.28). There was evidence that the association between sexual violence and ART adherence varied by pregnant/breastfeeding status (p = 0.004). Pregnant and breastfeeding women with a history of sexual violence had higher odds of suboptimal ART adherence (aOR: 4.11, 95% CI: 2.13-7.92) compared to pregnant and breastfeeding women without a history of sexual violence, while among non-pregnant and non-breastfeeding women, this association was attenuated (aOR: 1.39, 95% CI: 1.00-1.93). CONCLUSIONS: Sexual violence is associated with women's suboptimal ART adherence in sub-Saharan Africa, with a greater effect among pregnant and breastfeeding WLH. To improve women's HIV outcomes and to achieve the elimination of vertical transmission of HIV, violence prevention efforts within maternity services and HIV care and treatment should be a policy priority

Interventions to reduce gender-based violence among young people living with or affected by HIV/AIDS in low-income and middle-income countries

Objective(s): This study explored the effectiveness of gender-based violence (GBV) interventions on young people living with or affected by HIV in low- and middle-income countries (LMICs). Design: Systematic review and meta-analysis. Methods: We pre-registered a protocol, then searched thirteen databases and grey literature. We screened randomised and quasi-experimental studies (n = 2199) of young people (aged 10–24) living with or affected by HIV in LMICs. Outcomes were GBV and/or GBV-related attitudes. We appraised the data for risk of bias and quality of evidence. Narrative syntheses and multi-level random effects meta-analyses were conducted. Results: We included 18 studies evaluating 21 interventions. Intervention arms were categorised as: a) sexual health and social empowerment (SHSE) (n = 7); b) SHSE plus economic strengthening (n = 4); c) self-defence (n = 3); d) safer schools (n = 2); e) economic strengthening only (n = 2); f) GBV sensitisation (n = 2) and g) safer schools plus parenting (n = 1). Risk of bias was moderate/high and quality of evidence low. Narrative syntheses indicated promising effects on GBV exposure, but no or mixed effects on GBV perpetration and attitudes for self-defence and GBV sensitisation interventions. Safer schools interventions showed no effects. For SHSE interventions and SHSE plus economic strengthening, meta-analysis showed a small reduction in GBV exposure but not perpetration. Economic-only interventions had no overall effect. Conclusions: SHSE, SHSE plus and self-defence and gender sensitisation interventions may be effective for GBV exposure and GBV-related attitudes but not for GBV perpetration. However, the quality of evidence is poor. Future intervention research must include both boys and girls, adolescents living with HIV and key populations.</p

Impact of pre‐analytical sample handling factors on plasma biomarkers of Alzheimer's disease

An unmet need exists for reliable plasma biomarkers of amyloid pathology, in the clinical laboratory setting, to streamline diagnosis of Alzheimer's disease (AD). For routine clinical use, a biomarker must provide robust and reliable results under pre-analytical sample handling conditions. We investigated the impact of different pre-analytical sample handling procedures on the levels of seven plasma biomarkers in development for potential routine use in AD. Using (1) fresh (never frozen) and (2) previously frozen plasma, we evaluated the effects of (A) storage time and temperature, (B) freeze/thaw (F/T) cycles, (C) anticoagulants, (D) tube transfer, and (E) plastic tube types. Blood samples were prospectively collected from patients with cognitive impairment undergoing investigation in a memory clinic. β-amyloid 1-40 (Aβ40), β-amyloid 1-42 (Aβ42), apolipoprotein E4, glial fibrillary acidic protein, neurofilament light chain, phosphorylated-tau (phospho-tau) 181, and phospho-tau-217 were measured using Elecsys® plasma prototype immunoassays. Recovery signals for each plasma biomarker and sample handling parameter were calculated. For all plasma biomarkers measured, pre-analytical effects were comparable between fresh (never frozen) and previously frozen samples. All plasma biomarkers tested were stable for ≤24 h at 4°C when stored as whole blood and ethylenediaminetetraacetic acid (EDTA) plasma. Recovery signals were acceptable for up to five tube transfers, or two F/T cycles, and in both polypropylene and low-density polyethylene tubes. For all plasma biomarkers except Aβ42 and Aβ40, analyte levels were largely comparable between EDTA, lithium heparin, and sodium citrate tubes. Aβ42 and Aβ40 were most sensitive to pre-analytical handling, and the effects could only be partially compensated by the Aβ42/Aβ40 ratio. We provide recommendations for an optimal sample handling protocol for analysis of plasma biomarkers for amyloid pathology AD, to improve the reproducibility of future studies on plasma biomarkers assays and for potential use in routine clinical practice

Curcumin-primed human BMSC-derived extracellular vesicles reverse IL-1β-induced catabolic responses of OA chondrocytes by upregulating miR-126-3p

Background Curcumin has anti-inflammatory effects and qualifies as a potential candidate for the treatment of osteoarthritis (OA). However, curcumin has limited bioavailability. Extracellular vesicles (EVs) are released by multiple cell types and act as molecule carrier during intercellular communication. We assume that EVs can maintain bioavailability and stability of curcumin after encapsulation. Here, we evaluated modulatory effects of curcumin-primed human (h)BMSC-derived EVs (Cur-EVs) on IL-1β stimulated human osteoarthritic chondrocytes (OA-CH). Methods CellTiter-Blue Viability- (CTB), Caspase 3/7-, and live/dead assays were used to determine range of cytotoxic curcumin concentrations for hBMSC and OA-CH. Cur-EVs and control EVs were harvested from cell culture supernatants of hBMSC by ultracentrifugation. Western blotting (WB), transmission electron microscopy, and nanoparticle tracking analysis were performed to characterize the EVs. The intracellular incorporation of EVs derived from PHK26 labeled and curcumin-primed or control hBMSC was tested by adding the labeled EVs to OA-CH cultures. OA-CH were pre-stimulated with IL-1β, followed by Cur-EV and control EV treatment for 24 h and subsequent analysis of viability, apoptosis, and migration (scratch assay). Relative expression of selected anabolic and catabolic genes was assessed with qRT-PCR. Furthermore, WB was performed to evaluate phosphorylation of Erk1/2, PI3K/Akt, and p38MAPK in OA-CH. The effect of hsa-miR-126-3p expression on IL-1β-induced OA-CH was determined using CTB-, Caspase 3/7-, live/dead assays, and WB. Results Cur-EVs promoted viability and reduced apoptosis of IL-1β-stimulated OA-CH and attenuated IL-1β-induced inhibition of migration. Furthermore, Cur-EVs increased gene expression of BCL2, ACAN, SOX9, and COL2A1 and decreased gene expression of IL1B, IL6, MMP13, and COL10A1 in IL-1β-stimulated OA-CH. In addition, phosphorylation of Erk1/2, PI3K/Akt, and p38 MAPK, induced by IL-1β, is prevented by Cur-EVs. Cur-EVs increased IL-1β-reduced expression of hsa-miR-126-3p and hsa-miR-126-3p mimic reversed the effects of IL-1β. Conclusion Cur-EVs alleviated IL-1β-induced catabolic effects on OA-CH by promoting viability and migration, reducing apoptosis and phosphorylation of Erk1/2, PI3K/Akt, and p38 MAPK thereby modulating pro-inflammatory signaling pathways. Treatment of OA-CH with Cur-EVs is followed by upregulation of expression of hsa-miR-126-3p which is involved in modulation of anabolic response of OA-CH. EVs may be considered as promising drug delivery vehicles of curcumin helping to alleviate OA

Contrast and rate of light intensity decrease control directional swimming in the box jellyfish Tripedalia cystophora (Cnidaria, Cubomedusae)

Box jellyfish respond to visual stimuli by changing the dynamics and frequency of bell contractions. In this study, we determined how the contrast and the dimming time of a simple visual stimulus affected bell contraction dynamics in the box jellyfish Tripedalia cystophora. Animals were tethered in an experimental chamber where the vertical walls formed the light stimuli. Two neighbouring walls were darkened and the contraction of the bell was monitored by high-speed video. We found that (1) bell contraction frequency increased with increasing contrast and decreasing dimming time. Furthermore, (2) when increasing the contrast and decreasing the dimming time pulses with an off-centred opening had a better defined direction and (3) the number of centred pulses decreased. Only weak effects were found on the relative diameter of the contracted bell and no correlation was found for the duration of bell contraction. Our observations show that visual stimuli modulate swim speed in T. cystophora by changing the swim pulse frequency. Furthermore, the direction of swimming is better defined when the animal perceives a high-contrast, or fast dimming, stimulus

A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms.

High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the &lt;i&gt;LPA&lt;/i&gt; and 1 SNP in the &lt;i&gt;APOE&lt;/i&gt; gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the &lt;i&gt;LPA&lt;/i&gt; , 1 in the &lt;i&gt;APOE&lt;/i&gt; gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, &lt;i&gt;P&lt;/i&gt; = 3.35 × 10 &lt;sup&gt;-30&lt;/sup&gt; ). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the &lt;i&gt;APOE2&lt;/i&gt; -determining allele of rs7412 to be significantly associated with Lp(a) concentrations ( &lt;i&gt;P&lt;/i&gt; = 3.47 × 10 &lt;sup&gt;-10&lt;/sup&gt; ). Each &lt;i&gt;APOE2&lt;/i&gt; allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the &lt;i&gt;TLR2&lt;/i&gt; gene with Lp(a) ( &lt;i&gt;P&lt;/i&gt; = 3.4 × 10 &lt;sup&gt;-4&lt;/sup&gt; ). In summary, we identified a large number of independent SNPs in the &lt;i&gt;LPA&lt;/i&gt; gene region, as well as the &lt;i&gt;APOE2&lt;/i&gt; allele, to be significantly associated with Lp(a) concentrations

Age at Menarche and Its Association with the Metabolic Syndrome and Its Components: Results from the KORA F4 Study

OBJECTIVE: The metabolic syndrome is a major public health challenge and identifies persons at risk for diabetes and cardiovascular disease. The aim of this study was to examine the association between age at menarche and the metabolic syndrome (IDF and NCEP ATP III classification) and its components. DESIGN: 1536 women aged 32 to 81 years of the German population based KORA F4 study were investigated. Data was collected by standardized interviews, physical examinations, and whole blood and serum measurements. RESULTS: Young age at menarche was significantly associated with elevated body mass index (BMI), greater waist circumference, higher fasting glucose levels, and 2 hour glucose (oral glucose tolerance test), even after adjusting for the difference between current BMI and BMI at age 25. The significant effect on elevated triglycerides and systolic blood pressure was attenuated after adjustment for the BMI change. Age at menarche was inversely associated with the metabolic syndrome adjusting for age (p-values: <0.001 IDF, 0.003 NCEP classification) and additional potential confounders including lifestyle and reproductive history factors (p-values: 0.001, 0.005). Associations remain significant when additionally controlling for recollected BMI at age 25 (p-values: 0.008, 0.033) or the BMI change since age 25 (p-values: 0.005, 0.022). CONCLUSION: Young age at menarche might play a role in the development of the metabolic syndrome. This association is only partially mediated by weight gain and increased BMI. A history of early menarche may help to identify women at risk for the metabolic syndrome

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition